Abstract B28: Discovery of 2-acetylpyridine-[N-(3-hydroxy-2-naphthoyl)]hydrazone analogs as glycine N-methyltransferase (GNMT) inducers for the treatment of hepatocellular carcinoma (HCC)

Abstract

Abstract Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer mortality. Because of the late diagnosis, poor treatment options and high recurrence, the incidence still nearly equals to the mortality rate. Therefore, the discovery of novel therapeutic agents and/or drug combination strategies is urgently needed. Glycine N-methyltransferase (GNMT) is a tumor suppressor gene for HCC. Literatures revealed that the expression of GNMT is significantly down-regulated in HCC patients. Therefore, discovery of small molecule compounds that are able to enhance GNMT expression will have important implications for the treatment of HCC. Recently, we have identified a small molecule, 2-acetylpyridine-[N-(3-hydroxy-2-naphthoyl)]hydrazone (1), as a hit from a collective drug library containing more than 20,000 compounds using a GNMT gene expression-oriented screen platform. Preliminary results indicated that compound 1 is capable of inducing GNMT expression strongly with 7.57 folds to control in 2.5 micromole. In order to discover novel lead compounds based on the initial hit, we have synthesized more than 100 analogs of compound 1 and evaluated for their effects on GNMT promoter activity. Results indicated certain newly synthesized compounds are more active than compound 1. A comprehensive Structure-activity relationships (SAR) study will be presented. Citation Format: Cherng-Chyi Tzeng, Chih-Hua Tseng, Yeh-Long Chen. Discovery of 2-acetylpyridine-[N-(3-hydroxy-2-naphthoyl)]hydrazone analogs as glycine N-methyltransferase (GNMT) inducers for the treatment of hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B28.